Second-line Trials Research Articles

Prognostic value of response to first-line hydroxyurea according to IPSET stratification in essential thrombocythemia.

Hydroxyurea (HU) constitutes the first-line treatment in most patients with essential thrombocythemia (ET), but criteria for changing therapy are not clearly established. The prognostic value of complete hematological response (CHR) and resistance/intolerance to HU was assessed in 1080 patients from the Spanish Registry of ET, classified according to revised IPSET-Thrombosis stratification (Very low- n = 61, Low- n = 83, Intermediate- n = 261, and High-risk n = 675). With a median therapy duration of 5 years, CHR was registered in 720 (67%) patients (1-year probability 51%) and resistance/intolerance in 219 (20%) patients (5-years probability 13%). After correction by other risk factors, High-risk patients achieving CHR showed a reduced risk of arterial thrombosis (HR: 0.35, 95%CI: 0.2-0.6, p = 0.001) and a trend towards lower risk of venous thrombosis (HR: 0.45, 95%CI: 0.2-1.02, p = 0.06) whereas no association was observed for intermediate- or low-risk patients. In comparison with non-responders, intermediate- and high-risk patients achieving CHR had longer survival and lower myelofibrosis incidence. Development of resistance/intolerance to HU, mainly cytopenia, was associated with higher probability of myelofibrosis but no effect on survival or thrombotic risk was demonstrated. In conclusion, CHR with HU is associated with better outcomes and might be an early indicator for selecting candidates to second-line clinical trials.

Overcoming Osimertinib Resistance with AKT Inhibition in EGFRm-Driven Non-Small Cell Lung Cancer with PIK3CA/PTEN Alterations.

Osimertinib is an EGFR tyrosine kinase inhibitor indicated for the treatment of EGFR-mutated (EGFRm)-driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line-treated patients with EGFRm advanced non-small cell lung cancer (NSCLC). Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression. ctDNA profiling analysis of on-progression plasma samples from patients treated with osimertinib in both first- (phase III, FLAURA trial) and second-line trials (phase III, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations. In vitro and in vivo evidence using CRISPR-engineered NSCLC cell lines and patient-derived xenograft (PDX) models supports a functional role for PIK3CA and PTEN mutations in the development of osimertinib resistance. These alterations are functionally relevant as EGFRm NSCLC cells with engineered PIK3CA/AKT/PTEN alterations develop resistance to osimertinib and can be resensitized by treatment with the combination of osimertinib and the AKT inhibitor capivasertib. Moreover, xenograft and PDX in vivo models with PIK3CA/AKT/PTEN alterations display limited sensitivity to osimertinib relative to models without alterations, and in these double-mutant models, capivasertib and osimertinib combination elicits an improved antitumor effect versus osimertinib alone. Together, this approach offers a potential treatment strategy for patients with EGFRm-driven NSCLC who have a suboptimal response or develop resistance to osimertinib through PIK3CA/AKT/PTEN alterations. See related commentary by Vokes et al., p. 3968.

731P REWENEC: REal-World Evidence in NEC provides a reliable external control arm to avoid randomization for second-line clinical trials - A post hoc proof of concept analysis with the randomized phase II BEVANEC study

731P REWENEC: REal-World Evidence in NEC provides a reliable external control arm to avoid randomization for second-line clinical trials - A post hoc proof of concept analysis with the randomized phase II BEVANEC study

Continuation of Third-Generation Tyrosine Kinase Inhibitors in Second-Line Trials for EGFR-Mutated Non-Small-Cell Lung Cancer: Regulatory Considerations.

Continuation of Third-Generation Tyrosine Kinase Inhibitors in Second-Line Trials for EGFR-Mutated Non-Small-Cell Lung Cancer: Regulatory Considerations.

Breakthroughs in the Systemic Treatment of HER2-Positive Advanced/Metastatic Gastric Cancer: From Singlet Chemotherapy to Triple Combination.

Gastric cancer is heterogeneous in morphology, biology, genomics, and treatment response. Alterations in human epidermal growth factor receptor 2 (HER2) overexpression, microsatellite instability (MSI) status, programmed death-ligand 1 (PD-L1) levels, and fibroblast growth factor receptor 2 (FGFR2) can be used as biomarkers. Since the combination of fluoropyrimidine/platinum plus trastuzumab that was investigated in the ToGA trial was approved as a standard of care in HER2-positive patients in 2010, no other agents showed efficacy in the first- (HELOISE, LOGiC, JACOB trials) and second- (TyTAN, GATSBY, T-ACT trials) line treatments. Despite the success in treating breast cancer, various anti-HER2 agents, including a monoclonal antibody (pertuzumab), an antibody-drug conjugate (ADC; trastuzumab emtansine [T-DM1]), and a small molecule (lapatinib) failed to translate into clinical benefits until the KEYNOTE-811 (first-line) and DESTINY-Gastri01 (≥second-line) trials were conducted. The incorporation of HER2-directed treatment with immune checkpoint inhibitors in the form of a monoclonal antibody or ADC is now approved as a standard treatment. Despite the promising results of new agents (engineered monoclonal antibodies, bi-specific antibodies, fusion proteins, and small molecules) in the early phase of development, the management of HER2-positive gastric cancer requires further optimization to achieve precision medicine with a chemotherapeutic backbone. Treatment resistance is a complex process that can be overcome using a combination of chemotherapy, targeted agents, and immune checkpoint inhibitors, including novel agents. HER2 status must be reassessed in patients undergoing anti-HER2 treatment with disease progression after the first-line treatment. As a general guideline, patients who need systemic treatment should receive chemotherapy plus targeted agents, anti-angiogenic agents, immune checkpoint inhibitors, or their combinations.

Determinants of Treatment Benefit and Post-Treatment Survival for Patients with Hepatocellular Carcinoma Enrolled in Second-Line Trials after the Failure of Sorafenib Treatment.

Second-line treatments are standard care for advanced hepatocellular carcinoma (HCC) patients with preserved liver function who are intolerant of or progress on first-line therapy. However, determinants of treatment benefit and post-treatment survival (PTS) remain unknown. HCC patients previously treated with sorafenib and enrolled in second-line clinical trials were pooled according to the investigational treatment received and the subsequent regulatory approval: approved targeted agents and immune checkpoint inhibitors (AT) or other agents (OT) not subsequently approved. Univariate and multivariate analyses using Cox proportional hazards models established relationships among treatments received, clinical variables, and overall survival (OS) or PTS. For 174 patients (80 AT; 94 OT) analyzed, baseline factors for longer OS in multivariate analysis were second-line AT, absence of both portal vein thrombosis and extrahepatic spread (EHS). Treatment with AT (versus OT) was associated with significantly longer OS among patients with EHS (pinteraction = 0.005) and patients with low neutrophil-to-lymphocyte ratio (NLR; pinteraction = 0.032). Median PTS was 4.0 months (95% CI 2.8–5.3). At second-line treatment discontinuation, alpha-fetoprotein (AFP) levels <400 ng/dl, albumin-bilirubin (ALBI) grade 1, and enrolment onto subsequent trials independently predicted longer PTS. Treatment with AT, PVT, and EHS were prognostic factors for OS, while AFP, ALBI grade and enrolment onto a third-line trial were prognostic for PTS. Presence of EHS and low NLR were predictors of greater OS benefit from AT.

Retrospective evaluation of the role of gemcitabine-docetaxel in well-differentiated and dedifferentiated liposarcoma.

Well-differentiated (WDLPS) and dedifferentiated liposarcoma (DDLPS) account for the majority of liposarcomas. Although gemcitabine-docetaxel is used as second-line treatment in soft tissue sarcomas, its efficacy in WDLPS/DDLPS is not established. This study retrospectively analyzed the efficacy of gemcitabine regimens in WDLPS/DDLPS. All patients with WDLPS or DDLPS who received gemcitabine-based chemotherapy at our institution between September 2002 and January 2021 were included. Response was evaluated by an independent radiologist using RECIST 1.1. The Kaplan-Meier method was used to estimate distributions of survival outcomes and log-rank tests were used to compare survival outcomes between subgroups. Sixty-five WDLPS/DDLPS patients were included. Seven patients (10.8%) received a gemcitabine-based regimen more than once, totaling 72 treatments. The median age at the start of treatment was 66 years (range 32-80 years). Sixty-five (90.3%) regimens were gemcitabine-docetaxel, and 7 (9.7%) were gemcitabine alone. Majorities of treatments were for disease that was recurrent/metastatic (86.1%), was abdominal/retroperitoneal (83.3%), and had DDLPS components (88.9%), while 25.0% of treatments were for multifocal disease. The overall response rate was 9.7% (7/72). All responses were in patients with documented DDLPS. The median time to progression was 9.2months (95% CI 5.3-12.3months). The median overall survival from the start of therapy was 18.8months (95% CI 13.1-32.4months). Gemcitabine-docetaxel is an efficacious second-line treatment for DDLPS. Though cross study comparisons are not advisable, response to gemcitabine-docetaxel compares favorably to current standard options trabectedin and eribulin. This combination is a valid comparator arm for future second-line trials in DDLPS.

Metastatic Colorectal Cancer Outcomes by Age Among ARCAD First- and Second-Line Clinical Trials.

BackgroundWe evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials.MethodsAssociations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided.ResultsOlder adults comprised 16.4% of patients on first-line trials (870 total older adults aged >70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively).ConclusionsOlder adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy.

Oral SM-88 plus MPS, an effective yet less toxic treatment option in second-line advanced pancreatic cancer? Final phase II/III study results.

585 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a poor prognosis in refractory patients (pts). SM-88 Regimen, which comprises oral SM-88 (racemetyrosine, TYME Inc) plus 10mg methoxsalen, 50mg phenytoin, and 0.5mg sirolimus (MPS), has previously shown clinical activity in mPDAC. Methods: We report on the final results (primary objective, ORR) of our multicenter, prospective open-label phase II/III RCT (TYME-88-Panc Part 1, NCT03512756) of SM-88 Regimen in pts with mPDAC who had received at least one prior line of therapy. Subjects received either 230 mg BID or 460 mg BID PO SM-88; oral MPS QD was given at the same dose in both arms. Results: The last subject was enrolled on Mar 12, 2019. As of Sep 1, 2021, 49 subjects were randomized to either 460 (n = 26) or 920mg (n = 23) SM-88 plus MPS daily (ITT population); 37 were deemed evaluable after completing at least one 28-day cycle of treatment (min 23 days on treatment). The study population was heterogeneous: a majority (32/37 = 86.5%) had failed at least 2 prior lines of chemotherapy. Twenty pts (54.1%) had received FOLFIRINOX in the first line and 16 pts (43.2%), a gemcitabine-based regimen. For evaluable pts, the overall disease control rate (DCR) was 27.0%: 10/37 subjects reached RECIST v1.1-verified stable disease (SD); 3 of the 10 had RECIST-confirmed SD. For the 49 ITT pts, mOS was 3.4 months (mo). For the 37 evaluable pts, mOS was 3.9 mo, and mPFS was 1.9 mo. mOS, mPFS, and DCR did not differ significantly by SM-88 dose. mOS and mPFS trended toward improvement in subjects with fewer prior lines of treatment: for pts in the second line (n = 5), mOS was 8.1 mo (95% CI: 3.0 – no UL), and mPFS was 3.8 mo (95% CI: 0.9 – no UL). Although not confirmatory, exploratory analyses showed that circulating tumor cells decreased on SM-88 Regimen. SM-88 Regimen was well tolerated: only one pt of the 48 ever dosed (2.1%) experienced related SAEs on treatment (Grade 3 abdominal pain, Grade 4 hypotension), which were eventually resolved. Enrollment criteria specified ECOG &lt; = 2 at study entry; these scores were maintained or improved for most pts (24/37 = 64.9%) while on treatment. Overall health and quality of life (QOL) scores via EORTC QLQ-C30 were maintained, trending toward superiority for pts on 920 mg vs. 460 mg (p = ns). Conclusions: This final analysis confirmed that SM-88 Regimen was well tolerated, with pts attaining an overall DCR of 27%. Of note, for the small subset of pts treated in the second line, the mOS and mPFS were on par with results achieved in other published randomized PhIII second-line trials for mPDAC. Moreover, SM-88 Regimen exhibited far fewer Grade 3 and 4 AEs than other commonly used cytotoxic regimens in the second line. The 27% DCR, 8.1 mo mOS, and 3.8 mo mPFS in the second line, with minimal toxicity and preserved QOL, resulted in the active investigation of SM-88 Regimen in a large, ongoing second-line trial in mPDAC (NCT04229004). Clinical trial information: NCT03512756.

Immuno-oncology therapy in metastatic bladder cancer: A systematic review and network meta-analysis.

Three first line and three second-line clinical trials tested the effect of immunotherapy (IO) relative to standard chemotherapy (CT) on overall survival. However, network meta-analysis-based comparisons have not yet been presented. We addressed this void. To provide comparisons of overall survival (OS), progression-free survival (PFS), complete response (CR), partial response (PR), stable disease (SD), objective response rates (ORR), disease control rates (DCR) and adverse events (AEs) associated with 1st and 2nd line IO-based regimens. PubMed was searched for phase III randomized controlled trials from 2016 to 2021, including conference abstracts. We identified three first line [IMvigor130 (atezolizumab + CT vs atezolizumab vs CT), DANUBE (durvalumab vs durvalumab + tremelimumab vs CT), and KEYNOTE-361 (pembrolizumab + CT vs pembrolizumab vs CT)] and two second line [KEYNOTE-045 (pembrolizumab vs CT) and IMvigor211 (atezolizumab vs CT)] RCTs. Overall, 3255 and 1452 patients were respectively included in the first- and second-line settings. In 1st line setting, compared with CT, no IO-based regimen exhibited survival benefit. However, all exclusive IO regimens resulted in lower rates of grade 3+ AEs. In 2nd line setting, compared with CT, only pembrolizumab improved OS benefit. Conversely, atezolizumab only showed OS benefit in exploratory analyses. Compared to second-line CT, no experimental regimen (atezolizumab or pembrolizumab) exhibited statistically significant ORR benefit. Both pembrolizumab and atezolizumab resulted in lower rates of grade 3+ AEs compared to 2nd line CT. In metastatic UC, IO-based regimens do not hold a survival benefit relative to CT in 1st line setting. However, pembrolizumab holds a survival benefit in 2nd line compared to CT. Several IO-based clinical trials are ongoing and will provide more and possibly better treatment alternatives for locally advanced and metastatic UC.

Pattern of progression of intrahepatic cholangiocarcinoma: Implications for second-line clinical trials.

BackgroundIntrahepatic cholangiocarcinoma (iCCA) is the second most frequent liver cancer. The overall survival of iCCA and other biliary tract cancers (BTC) remains poor. Recently, the ABC‐06 trial reported the superiority of FOLFOX vs clinical observation as a second‐line treatment. Still, the survival benefit was less than expected. We hypothesized that the pattern of progression of iCCA can drive post‐progression survival (PPS), similar to hepatocellular carcinoma.MethodsMulticentre retrospective evaluation of consecutive iCCA patients who progressed after frontline systemic treatment with gemcitabine as monotherapy or in combination with platinum. Radiological assessment of progression was evaluated according to RECIST 1.1. The progression pattern was divided according to the presence/absence of new extrahepatic lesions (NEH).ResultsWe included 206 patients from 5 centres. The median OS was 14.1 months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were previous surgery 0.699 [0.509‐0.961], performance status >2.445 [1.788‐3.344], permanent first‐line discontinuation 16.072 [5.102‐50.633], registration of ascites 2.226 [1.448‐3.420] or bilirubin >3 mg/dl 3.004 [1.935‐4.664] during the follow‐up, and disease progression 2.523 [1.261‐5.050]. The appearance of NEH independently predicted OS 2.18 [1.55‐3.06] in patients with radiological progression. Amongst 138 patients eligible for second‐line treatment, PPS was 16.8 and 5.9 months in cases without and with NEH, respectively (P = .001). Progression owing to NEH lesions was an independent predictor of PPS 1.873 [1.333‐2.662], together with performance status, time to progression to the frontline treatment, bilirubin >3 mg/dl and ascites.ConclusionsPPS of iCCA is influenced by progression pattern, with important implications for second‐line trial design and analysis.

Toward a Treatment Sequencing Strategy: A Systematic Review of Treatment Regimens in Advanced Gastric Cancer/Gastroesophageal Junction Adenocarcinoma.

BackgroundPlatinum and fluoropyrimidine combinations typically comprise first‐line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second‐line (2L) and third‐line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA.Materials and MethodsWe conducted a systematic search of peer‐reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression‐free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively.ResultsIn 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2‐overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single‐agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination.ConclusionFor advanced G/GEA, review of trial results from 2009–2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity.Implications for PracticeThe rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first‐line platinum‐based regimens, identification of those with the best benefit‐to‐risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first‐line platinum/fluoropyrimidine combination and, for second‐line trials, patients with platinum/fluoropyrimidine‐refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first‐line regimen(s) followed by a strategy for subsequent regimens.

Will the clinical development of 4th-generation “double mutant active” ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?

Our current treatment paradigm of advanced anaplastic lymphoma kinase fusion (ALK+) non-small cell lung cancer (NSCLC) classifies the six currently approved ALK tyrosine kinase inhibitors (TKIs) into three generations. The 2nd-generation (2G) and 3rd-generation (3G) ALK TKIs are all “single mutant active” with varying potencies across a wide spectrum of acquired single ALK resistance mutations. There is a vigorous debate among clinicians which is the best upfront ALK TKI is for the first-line (1L) treatment of ALK+ NSCLC and the subsequent sequencing strategies whether it should be based on the presence of specific on-target ALK resistance mutations or not. Regardless, sequential use of “single mutant active” ALK TKIs will eventually lead to double ALK resistance mutations in cis. This has led to the creation of fourth generation (4G) “double mutant active” ALK TKIs such as TPX-0131 and NVL-655. We discuss the critical properties 4G ALK TKIs must possess to be clinically successful. We proposed conceptual first-line, second-line, and molecularly-based third-line registrational randomized clinical trials designed for these 4G ALK TKIs. How these 4G ALK TKIs would be used in the future will depend on which line of treatment the clinical trial design(s) is adopted provided the trial is positive. If approved, 4G ALK TKIs may usher in a new treatment paradigm for advanced ALK+ NSCLC that is based on classifying ALK TKIs based on the intrinsic functional capabilities (“singe mutant active” versus “double mutant active”) rather than the loosely-defined “generational” (first-, second-,third-,fourth-) classification and avoid the current clinical approaches of seemingly random sequential use of 2G and 3G ALK TKIs.

Trial eligibility in advanced hepatocellular carcinoma: Does it support clinical practice in underrepresented subgroups?

Although hepatocellular carcinoma is considered a highly lethal malignancy, recent therapeutic advances have been achieved during the last 10 years. This scenario resulted in an unprecedented improvement in survival for patients with advanced hepatocellular carcinoma, almost reaching 20-26 mo of overall survival after first-second line sequential treatment. The advent of the combination of atezolizumab with bevacizumab showed, for the first time, superiority over sorafenib with improvement in overall survival. However, first and second-line trials were correctly based on the premise that a strict selection of patients enhances the power to capture the positive effect of treatment by excluding competing risks for mortality such as liver failure, decompensated cirrhosis or other underlying medical conditions. As a result, the inclusion criteria used in clinical trials do not support the use of novel therapies in several real-world scenarios involving underrepresented subgroups, such as patients with unpreserved liver function, other comorbid conditions, a history of solid-organ transplantation, autoimmune disorders and those with a high risk of bleeding. The present text aims at discussing treatment strategies in these subgroups.

Pattern of progression of intrahepatic cholangiocarcinoma impacts on survival: Implications for second-line trials

Background and Aims: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent liver cancer, with an increasing incidence worldwide. Chemotherapy regimens based on gemcitabine and cisplatin are the frontline treatment for unresectable cases, but the overall survival remains poor. For this reason, many second-line trial are ongoing. Survival predictors upon progression are not established, differently from hepatocellular carcinoma, for which postprogression survival (PPS) is driven by the progression pattern.

Treatment and Survival Outcomes by Age Following Second-Line Therapy for Metastatic CRC (mCRC): Analysis of 13,149 Patients from the ARCAD Clinical Trials Program

Background: We evaluated the time to progression and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared to adults aged less than 70 years following progression on first-line clinical trials. Methods: Associations between clinical and disease characteristics, time to initial progression and rate of receipt of second-line therapy were evaluated. Time to progression and overall survival were compared between older and younger adults enrolled on second-line trials by Cox regression, adjusting for age, sex, ECOG PS, number of metastatic sites and presence of metastasis in the lung, liver or peritoneum. Findings: Older adults comprised 16·4% of enrolled patients on first-line trials. Older adults and those with ECOG PS >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariate analysis (p-value = 0·0117). Older and younger adults enrolled in second-line trials experience similar median time to progression and median overall survival (5·1 vs. 5·2 months; 11·6 vs. 12·4 months, respectively). Interpretation: Older adults are less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes for older vs younger adults following second-line therapy. Further study is needed to examine factors, including patient preference, along with the effects of comorbidities and functional status impacting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide more objective criteria regarding the risks and benefits of second-line therapy to aid decision making for older adults considering second-line therapy for metastatic colorectal cancer. Funding: The NCI GCC Spore Career Development Award (5P50CA127003-08) funded Dr. McCleary’s effort. The ARCAD Foundation funded data collection and analysis. Declaration of Interest: Alberto F Sobrero served on advisory boards and as a speaker at satellite symposia for Merck, Roche, Servier, Incyten, Sanofi, Bayer, Bristol Myers Squibb, Amgen, Eli Lilly, and Pierre Fabre. James M Cleary received research funding to his institution from Abbvie, Merus, Roche, and Bristol Myers Squib. He received research funding from Merck, Astrazeneca, Esperas Pharma, and Tesaro, received consulting fees from Bristol Myers Squibb, and received travel funding from Bristol Myers Squib. Volker Heinemann served as honoraria for Merck, Amgen, Roche, Sanofi, Sirtex, Servier, Pfizer. He served as a consultant or Merck, Amgen, Roche, Sanofi, Sirtex, and Bristol Myers Squibb. He served on an advisory board for Merck, Novartis, Boehringer Ingelheim, Servier, Pierre-Fabre, Celgene, and Terumo. He received research funding to his institution from Merck, Amgen, Roche, Sanofi, Pfizer, Boehringer-Ingelheim, Sirtex, Bayer, and Servier. He received travel funding from Merck, Roche, Amgen, Sirtex, Bayer, and Servier. Stuart M Lichtman is supported by the NCI Cancer Center Support Grant (P30CA008748). All other author have nothing to declare. Ethical Approval: All analyses were performed with approval from the local Institutional Review Board in accordance with the precepts of the Helsinki Declaration.

Receipt and survival outcomes by age following second-line therapy for metastatic CRC (mCRC): Analysis of 5,289 patients from the ARCAD Clinical Trials Program.

6 Background: Rates and survival outcomes for second-line therapy for mCRC for OA vs. YA are poorly understood. Methods: Pts with available subsequent treatment data after progression from 10 1st line trials were included. Associations between key clinical/disease characteristics, time to initial progression (TTiP) and rate of receipt of second-line therapy were evaluated. Time to progression (TTP) and overall survival (OS) were compared between OA and YA who were enrolled on second-line trials by Cox regression, adjusting for age, sex, ECOG PS, number of metastatic sites, presence of metastasis in lung/liver/peritoneum. Results: OA comprised 16.4% of first-line trials. OA and ECOG PS &gt;0 were less likely to receive second-line therapy than YA. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariate analysis (p=0.0117). OA enrolled in second-line trials experience similar mTTP and mOS as YA (5.1 vs. 5.2mos; 11.6 vs 12.4mos, respectively). Conclusions: OA are less likely to receive 2nd line therapy for mCRC. We did not observe a statistical difference in survival outcomes for OA vs. YA following second-line therapy. Further study is needed to examine unmeasured factors, including comorbidity and functional status given observed inferior outcomes among adults with ECOG PS &gt;0, and consideration given to inclusion of geriatric assessment to select OA likely to benefit from 2nd line therapy for mCRC. [Table: see text]

Management of recurrent and metastatic oral cavity cancer: Raising the bar a step higher

In recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN), the armamentarium of systemic anti-cancer modalities continues to grow in parallel with innovations in and better integration of local approaches. The backbone of cytotoxic chemotherapy remains cisplatin with 5-fluorouracil or a taxane. In contrast to cisplatin, the tumoricidal activity of carboplatin monotherapy is debatable. Adding the epidermal growth factor receptor (EGFR) inhibitor cetuximab to a platinum/5-fluorouracil doublet (the so-called EXTREME regimen) produced a statistically but also clinically significant improvement of survival and became thus the standard first-line palliative treatment in adequately fit patients. Interestingly, three large randomized trials (EXTREME, SPECTRUM, and ZALUTE) evaluating different anti-EGFR monoclonal antibodies (cetuximab, panitumumab, and zalutumumab, respectively) demonstrated preferential anti-tumour efficacy in patients with primary cancer in the oral cavity. Modern immunotherapy with immunomodulating antibodies, dubbed immune checkpoint inhibitors, such as anti-programmed cell death protein-1 (anti-PD-1) inhibitors nivolumab and pembrolizumab, showed unprecedented activity in one first-line (KEYNOTE-048) and several second-line trials (CheckMate-141, KEYNOTE-012, KEYNOTE-055, and KEYNOTE-040). In a minority of also heavily-pretreated patients, these agents generate long-lasting responses without the typical chemotherapy-related toxicity, however, at a price of a low overall response rate, rare but potentially life-threatening immune-related adverse events, the risk of hyperprogression, and high costs. In oligometastatic disease, emerging data indicate long-term benefit with locally ablative techniques including metastasectomy and stereotactic radiotherapy of pulmonary but also hepatic and other distant lesions. In the frame of highly-individualized cancer care, a particularly intriguing approach is a combination of systemic and local therapies.

A randomized phase II trial of second-line CAPTEM versus FOLFIRI in MGMT methylated, RAS mutated metastatic colorectal cancer (mCRC) patients.

3509 Background: Overall response rate (ORR) to temozolomide (TMZ) is ∼10% in refractory mCRC pts with MGMT methylation detected by qualitative assays, e.g. methylation-specific PCR (MSP). ORR to irinotecan/FOLFIRI in second-line trials was 4-16%. The efficacy of TMZ may be improved by its combinatorial use in earlier lines and molecular selection beyond MSP. Lack of MGMT expression by immunohistochemistry (IHC) and high MGMT % methylation by MethylBEAMing (MB) are prognostic for higher ORR/PFS in TMZ-treated pts. Methods: This multicenter, randomized phase 2 trial investigated PFS superiority of second-line CAPTEM (Arm A: capecitabine 750 mg/sqm bid days1-14/TMZ 75 mg/sqm bid days10-14q28 days) over FOLFIRI (arm B) in RAS mutated mCRC pts with MGMT methylation centrally confirmed by MSP. Eligible pts: ECOG PS 0-1, measurable disease, failure of 1st-line oxaliplatin-based tx (or relapse within 6 mos from oxaliplatin-based adjuvant tx). Randomization was stratified by time from the start of oxaliplatin-based therapy to PD ( &lt; /≥9 months); prior bevacizumab (yes/no). A one-sided log-rank test with a sample size of 82 pts (41 per arm) achieved 90% power at a 5% significance level to detect mPFS increase from 2 to 4 mos. Secondary endpoints: safety, QoL, OS, ORR. Exploratory endpoints: predictive value of MGMT IHC/MB. Results: From Nov 2014 to Feb 2019, 82 pts (arm A/B: 41/41) were enrolled in 18 Italian sites. Baseline characteristics (arm A/B): males 44/56%, median age 70/67, ECOG PS 0 54/51%, right-sidedness 37/39%, 1 metastatic site 44/34%, prior bevacizumab 68/66%, 1st-line PFS 9,4/10,2 months. At a median follow up of 26.6 mos, 70 PFS/46 OS events were collected. The mPFS was 3.6 vs 4.1 mos in arm A vs B (HR = 1.26;95%CI 0.78-2.02;p = 0.34) and mOS was 9.1 vs 14.2 mos (HR =1.08;95%CI 0.60-1.94;p = 0.79). ORR and DCR (arm A/B): 12/10% and 51/51%. Grade 3-4 adverse events: 15/44% (diarrhea 0/12%, stomatitis 0/7%, anemia 2/10%, neutropenia 2/22%, thrombocytopenia 7/0%). Neither MGMT IHC nor MB status were prognostic. MGMT IHC positive subgroup, arm A (n = 12) vs arm B (n = 22): mPFS, 2.0 vs 4.1 mos (HR = 2.06;95%CI 0.96-4.45;p = 0.06), mOS, 6.4 vs 10.6 mos (p = 0.78), ORR (0% vs 14%) and DCR (25% vs 55%;OR = 0.28;95%CI 0.06-1.31;p = 0.11). In MGMT IHC negative subgroup, no PFS/OS/ORR/DCR differences were noted between the two arms. P interaction IHCxArm: 0.171 for PFS, 0.917 for OS, 0.06 for DCR. Similar accuracy was achieved by MB. Conclusions: The use of TMZ should be explored by phase 3 trials enrolling MGMT IHC-negative +/- high MGMT % methylated mCRC. Clinical trial information: NCT02414009.

Vascular endothelial growth factor A (VEGF-A) amplification and long-term response to ramucirumab (ram) in metastatic gastric cancer (mGC): The VERA study.

3143 Background: The anti-VEGFR-2 monoclonal antibody ram, alone or with paclitaxel, is a cornerstone of second-line treatment of mGC. Even if about half patients do not benefit from ram, no predictive biomarkers have been identified so far. In TCGA, VEGF-A amplification was found in 7% of cases, almost exclusively in chromosomal instability subtype. We hypothesize that VEGF-A amplification in tumor cells could lead to autocrine/paracrine stimulation of tumor growth beside angiogenesis, potentially identifying a patients’ subgroup with exceptional responses to ram. Methods: VERA was a multicentric, prospective study based on a translational hypothesis. mGC patients were included according to the following criteria: 1) complete (CR) or partial response (PR) to single-agent ram; 2) &gt;6 months PFS to single-agent ram; 3) &gt;10 months PFS to paclitaxel+ram. According to a Fleming single-stage design, hypothesizing a prevalence of VEGF-A amplification of 1% and 15% among all-comers and exceptional responders, 20 exceptional responders were required to reject the null hypothesis of low prevalence of VEGF-A amplification, with alpha- and beta- errors of 0.05 and 0.10, respectively. VEGF-A amplification (defined as &gt;10% tumor cells with ≥10 VEGF-A copies, variably sized signal clusters or a ratio of VEGF-A gene to centromere of ≥2) was centrally assessed through fluorescent in situ hybridization on pre-treatment FFPE tumor tissue. Results: At 7 Italian Centers, we included 20 patients satisfying the 1st (n=1), 2nd (n=2), or 3rd (n=17) criterion. Clinical-pathological features were: M/F, 11/9; median age 63 years; gastric/GEJ, 17/3; intestinal/diffuse, 14/6, HER2+/HER2-, 4/16. Median PFS and overall survival to ram-based treatment were 15.6 and 25.7 months, with best response: CR/PR/SD, 0/10/10. VERA met its primary endpoint, revealing 3/20 (15%) tumors with VEGF-A amplification (1 case presenting big clusters, 1 small clusters and 1 with &gt;10% tumor cells with ≥10 VEGF-A copies). Conclusions: Validation analyses of first- and second-line randomized trials could confirm VEGF-A amplification as a biomarker of long-term response to ram-based treatment in mGC patients, advancing treatment personalization.